Various Studies Are Showing That Reactivation Of Dormant Epstein-Barr Virus Could Be What Is Responsible For COVID Severity As Well As Long COVID

A number of studies are emerging that indicate Epstein-Barr virus (EBV) reactivation may play a role both in the development of long COVID symptoms, as well as severe COVID-19 cases.

It has been found that Coronavirus disease 2019 (COVID-19) patients sometimes experience long-term symptoms following resolution of acute disease, including fatigue, brain fog, and rashes.
 
One study published in the peer reviewed journal: Pathogens, provides evidence linking Epstein-Barr virus reactivation to long COVID symptoms. https://www.mdpi.com/2076-0817/10/6/763
 
Dr Jeffrey E. Gold from the World Organization along with researchers from the Kahramanmaraş Sütçü İmam University-Turkey, Warren Alpert Medical School of Brown University-USA and the University of Georgia-USA aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-19 patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein–Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed.
 
The study team found the prevalence of long COVID symptoms to be 30.3% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms.
 
The team also found that 66.7% (20/30) of long COVID subjects versus 10% (2/20) of control subjects in the primary study group were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher’s exact test). A similar ratio was observed in a secondary group of 18 subjects 21–90 days after testing positive for COVID-19, indicating reactivation may occur soon after or concurrently with COVID-19 infection.
 
Dr Gold told Thailand Medical News, “We ran Epstein-Barr virus serological tests on COVID-19 patients at least 90 days after testing positive for SARS-CoV-2 infection, comparing EBV reactivation rates of those with long COVID symptoms to those who never experienced long COVID symptoms. We found over 73% of COVID-19 patients who were experiencing long Covid symptoms were also positive for EBV reactivation."
 
The study findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.
 
Yet another team of researchers found EBV reactivation may also be associated with COVID-19 severity.
 
The study was by Dr Ting Chen from the Renmin Hospital of Wuhan University-China
 
The study team initially started off with the objective to detect the Epstein–Barr virus (EBV) co-infection in coronavirus disease 2019 (COVID-19).
 
In a retrospective single-center study, the team included 67 COVID-19 patients with onset time within 2 we eks in Renmin Hospital of Wuhan University from January 9 to February 29, 2020. Patients were divided into EBV/SARS-CoV-2 co-infection group and SARS-CoV-2 infection alone group according to the serological results of EBV, and the characteristics differences between the two groups were compared. The median age was 37 years, with 35 (52.2%) females.
 
Among these COVID-19 patients, thirty-seven (55.2%) patients were seropositive for EBV viral capsid antigen (VCA) IgM antibody. EBV/SARS-CoV-2 co-infection patients had a 3.09-fold risk of having a fever symptom than SARS-CoV-2 infection alone patients (95% CI 1.11–8.56; P = 0.03). C-reactive protein (CRP) (P = 0.02) and the aspartate aminotransferase (AST) (P = 0.04) in EBV/SARS-CoV-2 co-infection patients were higher than that in SARS-CoV-2 infection alone patients. EBV/SARS-CoV-2 co-infection patients had a higher portion of corticosteroid use than the SARS-CoV-2 infection alone patients (P = 0.03).
 
The study team found a high incidence of EBV co-infection in COVID-19 patients. EBV/SARS-CoV-2 co-infection was associated with fever and increased inflammation. They found that EBV reactivation was associated with the severity of COVID-19.
 
The study findings were published in the peer reviewed journal: Scientific Reports. https://www.nature.com/articles/s41598-021-90351-y
 
Dr Gold said that more than 95% of health adults will test positive for latent EBV infection, identified by testing for the presence of EBV VCA IgG and/or EBV nuclear antigen 1 (EBNA-1) IgG.
 
EBV reactivation, on the other hand, is identified by further testing for the presence of EBV EA-D IgG, EBV VCA IgM, and/or circulating EBV DNA.
 
Co-author of the Pathogens study, Dr  David J. Hurley, PhD, a professor and molecular microbiologist at the University of Georgia said, "We found similar rates of EBV reactivation in those who had long COVID symptoms for months, as in those with long COVID symptoms that began just weeks after testing positive for COVID-19. This indicated to us that EBV reactivation likely occurs simultaneously or soon after COVID-19 infection."
 
Dr Gold further added that other diseases and stressors can also trigger EBV reactivation; this is not exclusive to COVID-19.
 
Alarmingly however, the inflammation response from SARS-CoV-2 infection, however, appears more successful than many other stressors at triggering EBV reactivation.
 
Although EBV reactivation may not be responsible for all cases of recurring fatigue or brain fog after recovering from COVID-19, evidence indicates that it likely plays a role in many or even most cases.
 
The study by Dr Gold’s team found that nearly one-third of 185 people surveyed who had tested positive for COVID-19 ended up with long haul symptoms, even some who were initially asymptomatic. This percentage of long term sequelae after COVID-19 infection was similar to the percentage found in a separate study Sequelae in Adults at 6 Months After COVID-19 Infection published in JAMA Network Open. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776560
 
The correlation between SARS-CoV-2 and EBV reactivation described in these studies open up new possibilities for the diagnosis and treatment of initial COVID-19 infection as well as long COVID.
 
The study team from the research published in Pathogens indicated that it may be prudent to test patients newly positive for COVID-19 for evidence of EBV reactivation indicated by positive EBV EA-D IgG, EBV VCA IgM, or serum EBV DNA tests. If patients show signs of EBV reactivation, they can be treated early to reduce the intensity and duration of EBV replication, which may help inhibit the development of long COVID.
 
Although, there is no available vaccine to prevent EBV infection, on July 26, 2021 a phase 1, open-label study to evaluate the safety and immunogenicity of an EBV vaccine sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) at NIH is expected to begin.
 
Dr Lawrence S. Young, PhD, a virologist at the University of Warwick speaking about the Pathogens study said,  "As evidence mounts supporting a role for EBV reactivation in the clinical manifestation of acute COVID-19, this study further implicates EBV in the development of long COVID. If a direct role for EBV reactivation in long COVID is supported by further studies, this would provide opportunities to improve the rational diagnosis of this condition and to consider the therapeutic value of anti-herpesvirus agents such as ganciclovir."
 
Thailand Medical News had brought up the issue about a correlation between EBV and SARS-CoV-2 as early as April 2020. https://www.thailandmedical.news/news/interesting-read-could-epstein-barr-virus-explain-why-certain-covid-19-patients-manifest-certain-symptoms-while-others-are-asymptomatic
 
It is also interesting to note that a study had also found that the drug Spironolactone possessed antiviral properties against EBV. https://www.thailandmedical.news/news/epstein-barr-virus-ebv-researchers-discover-mechanism-as-to-how-spironolactone-exhibits-antiviral-properties-on-the-virus
 
A few studies had also indicated that Spironolactone could help against SARS-CoV-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363620/
 
https://pubmed.ncbi.nlm.nih.gov/33477294/
 
https://www.frontiersin.org/articles/10.3389/fmed.2021.629176/full
 
https://www.sciencedirect.com/science/article/abs/pii/S0306987720321423
 
https://journals.lww.com/cardiovascularpharm/Fulltext/2021/03000/Is_Spironolactone_the_Preferred.7.aspx
 
https://www.mdpi.com/1424-8247/14/1/71
 
https://www.nejm.org/doi/full/10.1056/NEJMc2013707
 
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